Radiopaque esters of triiodophenoxy-alkanoic acids



United States Patent OfiFice 3,435,066 RADIOPAQUE ESTERS OF TRIIODOPHENOXY- ALKANOIC ACIDS Hans Snter, Dorflingen, and Hans Zutter, Schatfhausen, Switzerland, assignors to Eprova Limited, Schatfhausen,

Switzerland 1, 1965, Ser. No. 506,006

No Drawing. Filed Nov. Claims priority, application Switzerland, Dec. 23, 1964,

16,627/64; May 28, 1965,

Int. Cl. C07c 69/76; A61k 27/08 U.S. Cl. 260-473 ABSTRACT OF THE DISCLOSURE Esters of the formula 4 Claims R is alkyl having two This invention relates to esters of triiodophenoxyalkanoic acids which .are opaque to X-rays, and to the preparation and use of such esters.

It has been found that esters of the formula wherein R is hydrogen or methyl, R is alkyl having two to four carbon atoms, the combined number of carbon atoms in R and R is at least three, and R is lower .alkyl or lower-alkoxy-lower-alkyl, are highly opaque to X-rays, and are useful radiopaque ingredients for contrast media to be employed in the roentgenography of body cavities when they are liquid at noraml room .and body temperatures (about 10 to 40 C.), physiologically tolerated, substantially insoluble in water, and soluble in animal oils and fats.

The best radiopaque compounds of the invention are the esters of triiodophenoxycaproic acid with lower alkanols and lower alkoxyalkanols. They are surprisingly less toxic than the homologous esters of triiodophenoxybutyric acid.

The alcohol component of the esters of the invention is of relatively minor importance, but it must be chosen so as not to ailect the liquid state, the solubility characteristics, and the physiological properties of the material as set forth above. The alcohol component also aliects the viscosity of the compound, and the choice of the alcohol component may be determined by the requirements of the intended application. The ethyl ester of ot-2,4,6-triiodophenoxycaproic acid has been found to be suitable for all normal applications.

The esters of the lower alkanols, lower alkanols are liquids of relatively low viscosity which are capable of being distilled without decomposing, and are thus readily purified. They are readily soluble in or miscible with oil, fats, waxes, and the esters of higher fatty acid esters which are commonly employed as solvents or diluents in the application of radiopaque materials.

and lower alkoxy- 3,435,066 Patented Mar. 25, 1969 The compounds of the invention have unique advantages over known contrast media in the visualization of lymph vessels, but they are well suited for bronchography, hysterosalpingography, and the visualization of other body cavities. They may be employed in the pure and unmixed state, or they may be compounded with solvents and diluents as needed.

Because of their lack of solubility in water, the radiopaque compounds of the invention are not diluted by aqueous body fluid, such as lymph, but flow in the vessels from the point of injection, and their opactity does not'decrease with that distance from that point as is inherent in those conventional contrast media which form soluble salts with the alkaline matter in lymph. Yet, the compounds of the invention are resor-bed fairly rapidly and are excreted, after hydrolysis in the body, in the form of the readily water soluble salts of the corresponding acids. The bonds between the iodine atoms and the remainder of each compound is not disturbed by the metabolic process, and free phenolic hydroxyl groups are not formed in the body.

Although the new compounds have a very high iodine content, they do not produce the unfavorable side effects on the thyroid gland known to occur with less stable iodine compounds such as iodized oil. Because the iodine content is substantially higher than that of the conventional iodized oil, the overall amount of the new contrast medium necessary for a specific purpose is much lower than that of iodized oil.

The toxicity of the compounds of the invention is therefore very low, and they do not produce long-range afterelfects known to occur after lymphography with conventional radiopaque materials. The incidence of local reactions and of vessel occlusions is particularly low.

The ot-(2,4,6-triodophenoxy)-derivatives 0f the esters of fatty acids having a chain of less than four carbon atoms are not suitable as contrast media because they are crystalline solids (see J.A.C.S. 61 (1939) 61 and US. Patent No. 2,711,424), and are insoluble, or only sparingly soluble in fats and oil or in the esters of higher fatty acids which are commonly employed in formulating contrast media for lymphography. The compounds of the invention are liquids of surprisingly low viscosity so that they may even be employed without diluents for certain purposes, particularly for bronchography. If a further reduction of viscosity is desired, the necessary dilution may be achieved without loss of definition in the X- ray image produced by exposing a layer of photosensitive material to a beam of X-rays through the contrast medium in a body cavity because of the high iodine content of the esters of the invention. As has been mentioned above, the viscosity of the compounds of the invention depends in part on the nature of the substituents R and R in the above formula, and specific compounds of the invention may be chosen for specific applications. The fl-ethoxyethyl ester of a-(2,4,6-trii0dophenoXy)-caproic acid, for example, is more viscous than the corresponding ethyl ester.

The low viscosity of the compounds of the invention is of particular importance in lymphography. It is customary to prepare a patient for lymphography by injecting a contrast medium into a large lymph vessel. The contrast medium is preheated to body temperature (37 C.). The injection pressure must not be too high because of the danger of provoking embolism. Theinjection of the 25 ml. of the conventional iodized oil of lowest viscosity which are necessary for lymphography in an adult thus takes about two hours, and special automatic apparatus is necessary for maintaining a uniform, extremely slow rate of injection. The viscosity of the most fluid grade of iodized oil available at this time is 32.2 centipoises at 37 C. A 77.4% solution of ethyl rx-(2,4,6-triiodophenoxy)-caproate in ethyl la'urate has the same iodine content of 480 mg./ml. yet it has only a viscosity of 9.3 cp., and permits a correspondingly higher safe injection rate.

The following Table 1 shows data on iodine content and viscosity of various solutions of ethyl a-(2,4,6-tri iodophenoxy)-caproate in ethyl laurate, and of the radiopaque material free from solvent.

TABLE 1 Concentration of Iodine Temp, Viscosity, radiopaque material, content, C. centipoise mgJml. mgJrnl. 400 248 5. 3 600 372 30 7. 2 800 496 30 10. 3 900 560 30 12. 8 950 500 37 16 1, 270 787 37 32 No solvent. 1, 208 37 670 Table 2 shows a comparison of viscosities of ultrafiuid iodized oil and of a 774 mg./ml. solution of ethyl (it-(2,4,6- triiodophenoxy)-caproate in ethyl laurate at various temperatures, both liquids having the same iodine content of 480 mg./ ml.

Because of the lower viscosity of the radiopaque componds of the invention, the X-ray images of lymph vessels obtained with their use are superior, particularly in the resolution of fine detail, to those available with iodized oil.

Whereas iodized oil is stored in the body and can be detected by means of X-rays weeks and even months after the original injection, the compounds of the invention are resorbed rapidly. Ethyl triiodophenoxy-caproate, for example, is completely resorbed within 48 hours after injection into a white mouse. Iodized oil is still readily found seven days after injection under otherwise identical conditions.

Because the viscosity of pure ethyl triiodophenoxycaproate of the invention is 670 cp. at 37 C., it may be used for bronchography without diluents. It is well established that a contrast medium for bronchography should have a viscosity of about 400 to 900 cp. in order to prevent penetration into the alveoli of the lungs. Pure ethyl triiodocaproate and its concentrated solutions in suitable solvents such as ethyl laurate have been found to produce finely detailed X-ray bronchograms of animal lungs without any penetration of the contrast medium into the alveoli. No trace of the medium could be found five days after application.

The good control of viscosity which is possible with the compounds of the invention without unduly reducing their iodine content makes them valuable also for hysterosalpingography and myelography.

The compounds of the invention are readily prepared from 2,4,6-triiodophenol and its 3-alkyl homologs by reaction with esters of carboxylic acids having carbon chains of four to six members and a reactive substituent in the alpha-position which permits condensation with the phenol in the presence of a condensation agent. More specifically, the compounds of the invention are produced from esters of the formula wherein R and R are as defined above, and R is the radical of an acid such as halogen, methanesulfonyl, or toluenesulfonyl. The condensation agent is an alkaline material which is an acceptor for the free acid formed during condensation such as hydrogen halide, methanesulfonic acid, or toluene-sulfonic acid. The fatty acids having a chlorine, bromine, or iodine atom in the alpha position are most readily available, and are preferred.

As far as the corresponding free acids are available, the esters of the invention, of course, can be prepared by esterifying these acids with suitable alcohols in a conventional manner.

The following examples are further representative of the methods for preparing the compounds of the invention.

EXAMPLE 1 381 g. 2,4,6-triiodophenol were admixed to a sodium alcoholate solution prepared from 18.64 g. sodium and 850 ml. ethanol. 180.6 g. ethyl u-bromo-n-caproate were added, and the mixture was refluxed for about 20 to 30 hours.

The reaction product was cooled to ambient temperature and was filtered with suction, whereby much of the sodium bromide formed by the reaction was removed. The filtrate was evaporated in a vacuum. The residue was taken up in a large volume of ethyl ether, leaving the remainder of the sodium bromide as a crystalline solid material that was removed by filtration. Upon evaporation of the ether from the filtrate, there was obtained a liquid which was decolorized by shaking with an aqueous sodium bisul'fite solution.

The crude ethyl Ot-(2,4,6 triiodophenoxy)-caproate weighed 415 g. (83% yield). It was heated in the vacuum of a steam jet pump to C. for about one hour, and was then distilled in a high vacuum. The boiling point of the pure product at about 0.1 mm. Hg was ISO-190 C. and its density 1.947 g./ml. at 22 C. The yield of pure product was 338 g. (68%). Its identity was confirmed by microanalysis for iodine.

Analysis.-Calculated: I, 62.01%. Found: 1, 62.04%.

The pure compound is a slightly viscous oil which is practically colorless, insoluble in water, but miscible with almost all organic solvents in all proportions.

When applied to white mice by intraperitoneal injection, the toxicity of the compound (DL is above 2500 mg./ kg.

EXAMPLE 2 71 g. 2,4,6-triiodophenol were admixed to a sodium alcoholate solution prepared from 3.45 g. sodium and about 200250 ml. ethanol. 35.6 g. isopropyl a-bromo-ncaproate were added, and the resulting reaction mixture refluxed for 50 hours. The reaction mixture was worked up as in Example 1.

Isopropyl a-(2,4,6-triiodophenoxy)-caproate was obtained as a liquid boiling at about C. at about 0.05 mm. Hg, and identified by microanalysis for iodine.

Analysis.Calculated: I, 60.61%. Found: I, 60.49%.

The isopropyl ester has practically unlimited solubility in most organic solvents, including fats and oils. It is a slightly viscous oil whose toxicity (DL i.p.) to the white mouse is 7000 mg./ kg. The lower toxicity of the isopropyl ester, as compared to the ethyl ester, is accompanied by somewhat slower resorption and elimination believed due to steric hindrance at the ester bond, which reduces the saponification rate.

The isopropyl a-bromocaproate was not known heretofore, and is prepared by the reaction of equivalent amounts of a-bromocaproyl bromide with isopropanol in a benzene-pyridine solvent. It boils at approximately 100 C. at 14 mm. Hg.

EXAMPLE 3 of 14.5 g. ,8-methoxyethanol and 14.7 g. pyridine in 50 ml. benzene was added drop by drop with stirring, and the precipitated pyridine hydrobromide was filtered off. The filtrate was washed with aqueous sodium bicarbonate solution and then with water, dried, evaporated, and distilled in a vacuum. About 10 g. of the fi-methoxyethyl a-bromo-n-caproate were obtained. B.P. 106-107 C. at 4 mm.

67.5 g. 2,4,6-triiodophenol were admixed to a solution of 3.3 g. sodium in 270 ml. ethanol, and 36.2 g. B-methoxyethyl abromocaproate were added. The reaction mixture was refluxed for about 25 hours. Removal of the sodium bromide and further work-up as in Example 1 resulted in the recovery of 74 g. ,B-methoxyethyl tx-(2,4,6-triiodophenoxy)-caproate having a boiling temperature of ZOO-204 C. at about 0.1 mm. Hg.

Analysis.-Calculated: I, 59.12%. Found: I, 59.30%.

The solubility of this compound is the same as that of the ethyl and isopropyl esters. Its viscosity is somewhat higher which makes the compound particularly suitable for bronchography. It is resorbed substantially faster than the corresponding ethyl ester, and this rapid resorption is valuable in bronchography. Good results were obtained in lymphography of rabbits.

EXAMPLE 4 67.5 g. 2,4,6-triiodopheno1 were reacted with sodium ethylate and with 38.2 g. B-ethoxyethyl a-bromo-ncaproate as described in Example 3, the B-ethoxyethyl ester having been prepared in the same manner as the aforedescribed fl-methoxyethyl ester.

The ,B-ethoxyethyl a-(2,4,6-triiodophenoxy)-caproate obtained boils at about 200 C. at a pressure of 0.1 mm. Hg. It is insoluble in water and miscible with most organic solvents. It is readily resorbed by the organisms of warm-blooded animals.

EXAMPLE 5 48.6 g. 2,4,6-triiodocresol (2,4,6-triiodo 3 methylphenol) were admixed to a solution of 2.3 g. sodium in 200 ml. ethanol. 19.5 g. methyl a-bromo-n-butyrate were added, and the mixture obtained was refluxed with stirring for -20 hours. The sodium bromide formed was removed by filtration, and the filtrate was evaporated to dryness and taken up in ethyl ether. The ether solution was washed with dilute ice-cold sodium hydroxide solution, and thereafter repeatedly with water. The ether solution was reddish brown because of its iodine content, and was decolorized by shaking with sodium bisulfite or sodium thiosulfate solution. The residue obtained after evaporation of the ether was distilled in a high vacuum.

The pure ethyl u-(2,4,6 triiodo-3-methylphenoxy)- butyrate boiled at 167-170 C. at 0.1-0.08 mm. Hg. The yield was 36.5 g. (60%). The slightly viscous, colorless oil is insoluble in Water, but miscible in all proportions with most organic solvents.

The viscosity of the product can be adjusted by dilution with suitable solvents such as methyl laurate. The compound is well tolerated by white mice after intraperitoneal injection (LD 2460 mg./kg.). Resorption reaches 80% Within two days, and very good X-rays of the lymph vessels were obtained in injected rabbits.

EXAMPLE 6 194.4 g. 2,4,6-triiodocresol were admixed to a sodium alcoholate solut1on prepared from 9.2 g. sodium and about 800 ml. ethanol. 289.2 g. ethyl a-bromo-n-caproate were added, and the reaction mixture was refluxed for 20 to 30 hours. It was then worked up as in Example 5.

177 g. pure ethyl a-(2,4,6-triiodo-3-methylphenoxy)- caproate boiling at 175-177 C. at 0.08 mm. Hg were obtained. The product is a slightly viscous oil which is soluble in most organic solvents, also in fats practically in any proportion. The product Was found to be highly 7 suitable for lymphography by X-rays. It is well tolerated and quickly resorbed.

The higher homologs of 2,4,6-triiodo-3-methylphenol and of 2,4,6-triiodo-3,S-dimethylphenol react with a-bromobutyric and a-bromocaproic acid in a manner analogous to the several examples given hereinabove to produce the corresponding homologous esters. As far as these esters satisfy the requirements of being liquid, physiologically tolerated, substantially insoluble in water, and soluble in fats or oils, they are useful for the purposes of this invention. Since they are less readily accessible than unsubstituted triiodophenol or its monomethyl derivatives, and do not offer compensating advantages, they do not have economical value at this time.

Similar considerations make the esters of the corresponding derivatives of valeric acid, and of the several fatty acids having four to six carbon atoms in branched chains less desirable at this time than those of butyric and caproic acid which are dealt with in more detail in the preceding description of preferred embodiments of the invention, although the derivatives of valeric acid and of branched acids are effective radiopaque contrast media.

The compounds of the invention may be employed as radiopaque ingredients of contrast materials in the X-ray investigation of body cavities which further include additives and diluents known to be physiologically tolerated. Ethyl laurate is a preferred diluent for lymphography and bronchography, but other harmless organic solvents may also be employed, such as dimethylsulfoxide, ethanol, or the several polyhydric alcohols which are polymers of ethylene oxide (polyglycols). The concentration of the radiopaque compounds of the invention in such dilute solutions will normally be between about 250 and 1000 mg. per ml., but may be higher for special applications. The highest concentrations are preferred for bronchography.

The following contrast compositions are merely illustrative of the application of our compounds:

0 Ethyl a-(2,4,6-triiodophenoxy)-caproate g Ethyl laurate to make 100 ml.

Iodine content g./ml 0.56

Ethyl a-(2,4,6-triiodophenoxy)-caproate g Ethyl laurate to make ml.

Iodine content .g./ml 0.59

Ethyl a-(2,4,6-triiodophenoxy)-caproate g 127 Ethyl laurate to make 100 ml.

Iodine content g./ml. 0.79

Ethyl a-(2,4,6-triiodophenoxy)-caproate g 78 Ethyl laurate g 8.6 Dimethylsulfoxide g 11 Total volume ml 60 Iodine content g./ml 0.80

Ethyl u-(2,4,6-triiodophenoxy)caproate g 78 Ethyl laurate g 8.6 Ethanol g 10 Total volume ml 60 Iodine content g-./ml 0.80

Ethyl a-(2,4,6-triiodophenoxy)-caproate g 78 Ethanol ml 10 Total volume ml 50 Iodine content g./ml 0.97

7 (g) Ethyl u-(2,4,6-triiodophenoxy)-caproate g 78 Dimethylsulfoxide (11 g.) to make 50 ml.

Iodine content g./ml 0.97

Ethyl a-(2,4,6-triiodophenoxy)-caproate g 98.5 Dimethylsulfoxide (55 g.) to make 1 ml.

Iodine content g./ml 0.61

Ethyl a (2,4,6-triiodophenoxy)-caproate g 78 Polyethyleneglycol 400 g Dimethylsulfoxide (11 g.) to make 61.75 ml.

Iodine content g./rnl 0.80

The solutions listed above are sterilized in the usual manner prior to injection into the cavity to be visualized by X-ray inspection in a conventional manner. Solutions (a) to (e) are particularly suitable for lymphography, while the solutions (if) to (j) have been found very successful in bronchoscopy.

The ethyl ot-(2,4,6-triiodophenoxy)-caproate in the compositions (a) to (f) may be replaced by analogous amounts of the other compounds referred to in the above examples to produce substantially the same effects.

Complete lymphography in a human adult requires an amount of rdiopaque material of the invention containing about 6 to 12 g. iodine. About 5 g. bound iodine are needed for a full bronchography.

8 What is claimed is: 1. An ester of the formula Br I l l I O(|)HCOO-R l R2 I wherein R is hydrogen or methyl, R is alkyl having two to four carbon atoms, the combined number of carbon atoms in R and R being at least three, and R being lower alkyl or lower-alkoxy-lower-alkyl.

2. An ester as set forth in claim 1, wherein R is hydrogen, R is n-butyl, and R is lower alkyl.

3. An ester as set forth in claim 2, wherein R is ethyl. 4. An ester as set forth in claim 2, wherein R is isopropyl.

References Cited FOREIGN PATENTS 338,274 6/ 9 Switzerland. 775,811 5/1957 Great Britain. 591,939 2/1960 Canada.

448,3 67 5/ 1948 Canada. 338,274 6/ 1959 Switzerland.

LORRAINE A. WELNBERGER, Primary Examiner. D. STENZEL, Assistant Examiner.

US. Cl. X.R. 

